VEGF is a secreted polypeptide which is essential for formation of the vascular system in embryogenesis and plays a major role in angiogenesis in a variety of disease states. VEGF expression is upregulated by hypoxia and several cytokines in diverse cell types, and elicits multiple biological activities in vivo and in vitro including the differentiation, proliferation, migration and survival of endothelial cells, increased vascular permeability, monocyte migration, and increased endothelial production of the vasodilatory factors NO and prostacyclin. VEGF-induced NO and prostacyclin production are in turn implicated in both angiogenesis and several vascular protective effects of VEGF, including increased permeability, and inhibition of intimal vascular smooth muscle cell hyperplasia and thrombosis.
Human VEGF exists in multiple isoforms of 121, 145, 165, 189 and 206 amino acids, generated by alternative mRNA splicing, of which VEGF121, VEGF145 and VEGF165 are known to be secreted and biologically active forms. Two distinct protein tyrosine kinase receptors for VEGF have been identified, Flt-1 (VEGFR1) and KDR/Flk-1 (VEGFR2). KDR/flk-1 is thought to be the receptor which primarily mediates the mitogenic effects of VEGF in endothelial cells and angiogenesis in vivo; the function of Flt-1 in endothelial cells is unknown. A non-tyrosine kinase transmembrane protein, neuropilin-1 (NP-1), has been identified as an additional receptor for VEGF which specifically binds VEGF165, and enhances binding of VEGF165 to VEGFR2. The role of NP-1 in mediating biological effects of VEGF is still largely unknown.